PROSTATE CANCER 3 (PCA3) REPRESENTS A CLINICALLY MEANINGFUL PREDICTOR OF PROSTATE CANCER AT REPEAT BIOPSY

PROSTATE CANCER 3 (PCA3) REPRESENTS A CLINICALLY MEANINGFUL PREDICTOR OF PROSTATE CANCER AT REPEAT BIOPSY

724 THE JOURNAL OF UROLOGY® 2102 EARLY POSTOPERATIVE ULTRASENSITIVE PSA LEVEL PREDICTS RECURRENCE OF PROSTATE CANCER AFTER RADICAL PROSTATECTOMY Kev...

238KB Sizes 1 Downloads 75 Views

724

THE JOURNAL OF UROLOGY®

2102 EARLY POSTOPERATIVE ULTRASENSITIVE PSA LEVEL PREDICTS RECURRENCE OF PROSTATE CANCER AFTER RADICAL PROSTATECTOMY Kevin M Slawin*, Leif Peterson, John Dodge, Thomas M Wheeler, Jimmy Xie, Qiupeng Guo, Bothland Ung. Houston, TX. INTRODUCTION AND OBJECTIVE: The risk of a detectable and rising serum prostate specific antigen (PSA) level, termed biochemical recurrence (BCR), after prostatectomy can be predicted by FOLQLFDODQGSDWKRORJLFSDUDPHWHUVLGHQWL¿HGDWSURVWDWHFWRP\EXWWKH DFFXUDF\RISUHGLFWLRQUHPDLQVLPSUHFLVH0RUHDFFXUDWHVWUDWL¿FDWLRQ RI ULVN ZRXOG DOORZ D PRUH HI¿FLHQW DQG FRVWHIIHFWLYH DSSURDFK WR monitoring patients after prostatectomy. We studied the value of early postoperative ultrasensitive PSA levels for predicting BCR after prostatectomy. METHODS: We studied 792 consecutive patients who XQGHUZHQWUDGLFDOSURVWDWHFWRP\IRUFOLQLFDOO\ORFDOL]HGSURVWDWHFDQFHU performed by a single surgeon and who were followed routinely using an ultrasensitive PSA assay (Immulite 2000 3rd Generation PSA, Siemens Medical) beginning at least six weeks after surgery. Cox proportional KD]DUGV PRGHOLQJ LQFOXGLQJ VWDQGDUG SRVWRSHUDWLYH SDUDPHWHUV EXW DOVRLQFOXGLQJVWUDWL¿FDWLRQE\WKH¿UVWSRVWRSHUDWLYHXOWUDVHQVLWLYH36$ OHYHO”DQG”ZDVSHUIRUPHG7KHPHGLDQIROORZXSZDV months (IQR 11-43.8). RESULTS: 309 (39%) and 615 (77.7%) patients achieved D•ZHHNSRVWRSHUDWLYHX36$RI”QJP/DQG”QJP/ UHVSHFWLYHO\&R[SURSRUWLRQDOKD]DUGVPRGHOLQJWRSUHGLFWUHFXUUHQFH GHPRQVWUDWHG WKDW WKH IROORZLQJ YDULDEOHV ZHUH VLJQL¿FDQW SUHGLFWRUV of recurrence: pre-prostatectomy PSA, prostatectomy Gleason score, extracapsular extension, surgical margin status, lymph node involvement, and early postoperative PSA level. In this model, using a %&5WKUHVKROGGH¿QLWLRQRIDQGULVLQJRUVDOYDJHWKHUDS\WKH+D]DUG 5DWLRIRUUHFXUUHQFHZKHQWKH¿UVWSRVWRSHUDWLYHX36$OHYHOZDV” ZDV &,S DQGZKHQ”ZDV  CI 0.1- 0.34, p < 0.005). CONCLUSIONS: Early postoperative ultrasensitive PSA level is a powerful predictor of BCR after prostatectomy even when controlling for other known predictive variables. Patients who achieve an XOWUDVHQVLWLYH36$OHYHORI”E\VL[ZHHNVDIWHUVXUJHU\DUHDWYHU\ low risk for BCR and may be followed less frequently after surgery. On the other hand, patients who fail to achieve an ultrasensitive PSA level RI”DUHDWVLJQL¿FDQWO\KLJKHUULVNRI%&5DQGVKRXOGEHIROORZHG more closely so that early intervention with salvage radiotherapy may be offered, when it is likely to be more effective. Source of Funding: None

2103 PREDICTIVE VALUE OF PROSTATE SPECIFIC ANTIGEN VELOCITY IN THE DIAGNOSIS OF PROSTATE CANCER: RESULTS OF THE TYROL SCREENING PROJECT Jasmin Bektic*, Alexandre E Pelzer, Daniela Colleselli, Georg Schafer, Georg Bartsch, Wolfgang Horninger. Innsbruck, Austria. INTRODUCTION AND OBJECTIVE: We evaluate the SUHGLFWLYHYDOXHRISURVWDWHVSHFL¿FDQWLJHQYHORFLW\ 36$9 LQUHJDUG to prostate cancer diagnosis in volunteers who participated in the Tyrol PSA Screening Project. METHODS: The study population included 3,719 men who had undergone at least one ultrasound-guided prostate biopsy between January 1993 and July 2006 and in whom pathologic examination yielded prostate cancer or showed no evidence of prostatic malignancy. Due to changes in the biopsy protocol, the number of biopsies obtained increased from 6 cores (January 1993 to October 1995) to 10 (November 1995 to March 2000) and then to 15 cores (March 2000 to July 2006). Serial PSA measurements performed over 4 years prior to biopsy were evaluated and PSAV was calculated. Using a cut-off value of 0.4 ng/ml/ \UZHGHWHUPLQHGVHQVLWLYLW\VSHFL¿FLW\SRVLWLYHDQGQHJDWLYHSUHGLFWLYH values (PPV, NPV). RESULTS: The study group included 2600 men with no evidence of prostate cancer and 528 cancer patients. In men with no evidence of prostate cancer median PSAV remained 0.0 ng/ml/yr over time. In patients with biopsy-proven prostate cancers, however, median

Vol. 179, No. 4, Supplement, Wednesday, May 21, 2008

PSAV at four years prior to biopsy was 0.58 and increases to 0.98 ng/ml/ \UDWWKHWLPHRIGLDJQRVLV7KHVHQVLWLYLW\VSHFL¿FLW\SRVLWLYHSUHGLFWLYH value (PPV), and negative predictive value (NPV) for determining the prostate cancer by using the cut-off value of PSAV of 0.4 ng/ml/yr were 58.7, 94.7, 69.2 and 91.9 %, respectively.

positive negative

true positive (n) 310 false negative (n) 218

false positive (n) 138 true negative (n) 2462

sensitivity (%)

VSHFL¿FLW\ 

58.7

94.7

PPV (%) 69.2 NPV (%) 91.9

CONCLUSIONS: The use of PSAV in the increasing number of men with serial PSA measurements obtained in a screening setting may aid in diagnosing prostate cancer and spare unnecessary prostate biopsies. Source of Funding: None

2104 PROSTATE CANCER 3 (PCA3) REPRESENTS A CLINICALLY MEANINGFUL PREDICTOR OF PROSTATE CANCER AT REPEAT BIOPSY Alexander Haese*, Felix K H Chun, Alexandre de la Taille, Hendrik van Poppel, Michael Marberger, Peter F Mulders, Clement-Claude C Abbou, Arnulf Stenzl, Hartwig Huland, Martina Tinzl, Mesut Remzi, Suzan Feyerabend, Martijn Van Gils, Alexander Stillebroer, Jack A Schalken. Hamburg, Germany, Paris, France, Leuven, Belgium, Vienna, Austria, Nijmegen, The Netherlands, and Tuebingen, Germany. INTRODUCTION AND OBJECTIVE: The urinary prostate cancer 3 (PCA 3) marker represents a hopeful novel molecular marker WRLPSURYHVSHFL¿FLW\RISURVWDWHFDQFHUGHWHFWLRQ:HLQYHVWLJDWHGIRU WKH¿UVWWLPHZKHWKHUWKHXULQDU\SURVWDWHFDQFHU 3&$ PDUNHULV capable to withstand most stringent uni- and multivariable analyses to display its discriminative as well as its informative character. METHODS: A multi-institutional dataset consisting of 432 men subjected to a repeat prostate biopsy of 6 different European centers was used. Uni- and multivariable logistic regression models to predict SUHVHQFH RI SURVWDWH FDQFHU DW UHSHDW ELRSV\ ZHUH ¿WWHG XVLQJ DJH DRE, PSA, %fPSA, prostate volume and PCA 3. Bootstrap-corrected SUHGLFWLYH DFFXUDF\ ZDV TXDQWL¿HG XVLQJ$8& HVWLPDWHV LQ PRGHOV with and without PCA 3. This method was selected with the intent of quantifying the increment in predictive accuracy, associated with the addition of PCA 3 to all base predictor variables. PCA 3 was coded as a cubic spline to allow non-linear effects and to obviate the limitations associated with the use of categorical cut-offs. Differences in predictive DFFXUDF\ZHUHFRPSDUHGXVLQJWKH0DQWHO+DHQV]HOWHVW RESULTS: Prostate cancer was detected in 120 (27.8%) PHQ 3&$  UHSUHVHQWHG D VWDWLVWLFDOO\ VLJQL¿FDQW DQG LQGHSHQGHQW predictor of prostate cancer at repeat biopsy (p=0.006). Additionally, PCA 3 represented the most informative univariable predictor and was capable of increasing predictive accuracy in multivariable models by ZKLFKZDVKLJKO\VLJQL¿FDQW S  CONCLUSIONS: In the repeat biopsy setting, PCA 3 outperformed all traditional risk factors such as age, DRE or %fPSA RUWRWDO36$:HGHPRQVWUDWHIRUWKH¿UVWWLPHWKDWLQFOXVLRQRI3&$ LQWR PXOWLYDULDEOH PRGHOV LQFUHDVHG SUHGLFWLYH DFFXUDF\ VLJQL¿FDQWO\ Thus, PCA 3 meets all criteria of a novel, clinically useful marker and should be considered in future clinical practice and applications such as nomograms.

Vol. 179, No. 4, Supplement, Wednesday, May 21, 2008

THE JOURNAL OF UROLOGY®

725

2106

Source of Funding: None

2105 IMPROVED PREDICTION OF PROSTATE BIOPSY OUTCOME USING PCA3, TMPRSS2:ERG GENE FUSIONS AND SERUM PSA Sheila M Aubin*, Siobhan Miick, Sarah Williamsen, Petrea Hodge, Jessica Meinke, Amy Blase, Daphne Hessels, Jack A Schalken, Harry Rittenhouse, Jack Groskopf. San Diego, CA, and Nijmegen, The Netherlands. INTRODUCTION AND OBJECTIVE: There is an existing need for prostate cancer (PCa) markers with greater diagnostic accuracy. Recently, qualitative detection of TMPRSS2(T2):ERG gene fusions in urine sediments has been shown to increase sensitivity when used with a Prostate Cancer Gene 3 (PCA3) test. (Hessels, et al. Clin. Canc. Research 13:5103). In this research study, we evaluated the combination of PCA3, T2:ERG mRNA and serum PSA (sPSA) assays for predicting prostate biopsy outcome. METHODS: Urine specimens were collected following DRE from men scheduled for biopsy (n = 105). Urine sediments were prepared by centrifugation, washed with PBS, and total RNA isolated E\7UL]ROH[WUDFWLRQ4XDQWLWDWLYH3&$DQGTXDOLWDWLYH7(5*P51$ DVVD\V ZHUH SHUIRUPHG XVLQJ 7UDQVFULSWLRQPHGLDWHG DPSOL¿FDWLRQ The performance of the combined markers was assessed using logistic regression (LR) analysis, or by setting individual cutoffs and designating the overall result as positive if any of the three test results was positive. RESULTS: PCa was detected in 32/105 men. Based on Receiver Operator Curve analyses, the area under the curve increased from 0.65 (PCA3 alone) to 0.77 (PCA3 + T2:ERG) and 0.80 (PCA3 + T2:ERG + sPSA). For this cohort, PCA3 alone yielded a sensitivity of 53% DQGVSHFL¿FLW\$GGLQJWKH7(5*UHVXOWLQFUHDVHGWKHVHQVLWLYLW\ WRZLWKRXWDIIHFWLQJVSHFL¿FLW\7KHFRPELQDWLRQRI3&$7(5* DQGV36$\LHOGHGWKHEHVWUHVXOWVZLWKVHQVLWLYLW\DQGVSHFL¿FLW\RI and 77%, respectively. Both the LR and individual cut-off approaches SURGXFHGWKHVDPHVHQVLWLYLW\DQGVSHFL¿FLW\UHVXOWV &21&/86,2167KHVHGDWDFRQ¿UPSUHYLRXVUHVXOWVVKRZLQJ synergy between PCA3 and T2:ERG assays for predicting biopsy outcome, and suggest that further improvement in diagnostic accuracy could be achieved using a nomogram that also incorporates sPSA.

FIELD EFFECT REVEALED BY 3D-MAPPING OF TELOMERE DNA CONTENT AND ALLELIC IMBALANCE IN WHOLE MOUNT PROSTATES &KULVWRSKHU0+HDSK\ (ULF*7UHDW7ULVKD0)OHHW0DUFR%LVRI¿ $QWKRQ\<6PLWK0LFKDHO6'DYLV(GJDU*)LVFKHU-HIIUH\.*ULI¿WK Albuquerque, NM. INTRODUCTION AND OBJECTIVE: Critically shortened telomeres generate genomic instability, which is manifested by the presence of allelic imbalance (AI). We have shown that telomere DNA content (TC), a proxy for telomere length, measured in tumor tissues predicts prostate cancer survival. Additionally, we observed telomere alterations in histologically normal prostate tissues adjacent to carcinomas, implying a reservoir of genetically unstable cell populations that may represent fertile ground for tumorigenesis. We investigated this ³¿HOGHIIHFW´E\GHWHUPLQLQJVSDWLDOGLVWULEXWLRQVRI7&DQG$,LQZKROH mount prostates. METHODS: Slot blot titration assay was used to quantitate TC in microdissected tissue consisting of 105 normal epithelium without benign prostatic hyperplasia (BPH), 26 normal stroma without BPH, 188 BPH, 4 prostatic intraepithelial neoplasia (PIN), and 35 tumor samples from eight prostate specimens. The positional relationships of the samples were mapped on scanned images of whole mount sections. The extent of AI was determined in 33 normal epithelium without BPH, 10 normal stroma without BPH, 83 BPH, 3 PIN, and 8 tumor samples. Comparisons of TC distributions in cancerous vs. non-cancerous prostates were evaluated using the Kruskal-Wallis test. RESULTS: Tumor-adjacent, histologically normal tissues displayed heterogeneous TC and AI patterns. The TC distribution in BPH differed in cancerous vs. non-cancerous prostates. Compared to TC in a QRUPDOSURVWDWH Q 7&PHDQ  %3+VDPSOHVIURPDFDQFHURXV SURVWDWHGLVSOD\HGWHORPHUHVKRUWHQLQJ Q 7&PHDQ  VLPLODUWR WKHWXPRUWLVVXH Q 7&PHDQ  ZKHUHDV%3+VDPSOHVIURP D QRQFDQFHURXV SURVWDWH GLVSOD\HG WHORPHUH HORQJDWLRQ Q  7& PHDQ S $GGLWLRQDOO\$,ZDVSUHVHQWLQRIWKH%3+ samples, indicating the presence of genomic instability. CONCLUSIONS: Spatial distributions of TC and AI in whole PRXQWSURVWDWHVLQGLFDWHDFRPSOH[³¿HOGHIIHFW´ZLWKYDU\LQJFRQWULEXWLRQV from both cancer and BPH. The observation that telomere dysregulation RFFXUVLQ¿HOGVRIKLVWRORJLFDOO\QRUPDOWLVVXHVVXUURXQGLQJWKHWXPRU is of clinical importance, as it may have implications for the diagnosis, prognosis and treatment of prostate cancer.

Source of Funding: None

Source of Funding: This study was supported by the National Institutes of Health Grant RR0164880 and the University of New Mexico Cancer Center Support Grant NIH/NCI P30CA118110.